Acid Chlorides
Acid chlorides are important intermediates for a variety of bulk chemicals ranging from drug molecules to surfactants for personal cleansing.
Acid chlorides are synthesized by reacting the organic acids with chlorinating agents such as thionyl chloride (SOCl2), phosgene (COCl2), phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5) or oxalyl chloride (COCl)2. This reaction is preferably carried out in the presence of a catalyst, typically N, N-di-substituted formamides and acetamides. The catalysis by formamide type of catalyst goes via Vilsmeier salt (complex) as depicted below:

Very commonly, the acid chloride product is purified by distillation. One such method is disclosed in U.S. Pat. No. 4,204,916 (Stauffer Chemical Co., 1980) in which the acid chloride is distilled at sub-atmospheric pressure in the presence of a distillation improvement additive which is a mineral oil or an organopolysiloxane. However, such distillation processes are not only energy-intensive and time-consuming, but they also end up generating undistilled residues that need to be disposed off. This loss of product in distillation process is inevitable. Decomposition of dissolved catalyst complex (Vilsmeier salt) during distillation generates undesired impurities. Also, not all organic acid chlorides are amenable to distillation step for purification.
There are several reports in literature where the product, the acid chloride, is isolated from the catalyst complex by phase separation (product as one phase and the Vilsmeier complex as the other phase). This technique for isolation of the product from the catalyst is applicable to the organic acid chlorides which are liquids and hence can phase-separate from the dark colored Vilsmeier complex. The clean separation of phases is not possible and one can refer to various attempts made in the literature to improve the separation process (U.S. Pat. No. 5,166,427 (1992), U.S. Pat. No. 5,200,560 (1993), U.S. Pat. No. 5,247,105 (1993), U.S. Pat. No. 6,770,783 (2004), U.S. Pat. No. 6,727,384 (2004))
U.S. Pat. No. 5,166,427 provides a process for preparation of an acyl chloride by reacting equimolar amounts of carboxylic acid and phosgene at a temperature between 0-200° C., in the presence of a catalyst adduct of phosgene and N, N-dialkyl formamide (in an amount of 5-200 mol %, based on the carboxylic acid), so as to form two phases, an upper product phase and a lower catalyst adduct phase which can be recycled.
U.S. Pat. No. 5,200,560 teaches a process for preparation of carboxylic acid chloride by reacting carboxylic acid with liquid or gaseous phosgene in the presence of a catalyst adduct of phosgene and N, N-disubstituted formamide. The amount of ‘phosgene Vilsmeier complex’ is kept between 20-70% molar, based on the formamide.
U.S. Pat. No. 5,247,105 provides a process for preparing a fatty acid chloride. The process comprises allowing phase separation to provide an upper organic layer containing the fatty acid halide and a lower layer of the Vilsmeier complex. The phase separation is effected by carrying out the reaction in the presence of 0.02-0.5 wt % of a fatty acid nitrogen derivative such as fatty nitriles, primary, secondary or tertiary amines, diamines, quaternary ammonium salts, fatty amine oxides, and mono or di-substituted fatty amides.
U.S. Pat. No. 6,727,384 discloses a method for purifying carbonyl chlorides, obtained by a reaction between carboxylic acids and phosgene/thionyl chloride, by treating the reaction product with a hydrohalide of carboxamide such as N, N-dimethyl formamide hydrochloride at a temperature of between −15 to 80° C. The acid chlorides are then phase separated from the catalyst complex. There is an improvement in the color of the acid chloride compared to the original crude, however, the hydrohalide (HCl) content increase which is subsequently driven off by purging nitrogen, to get the desired quality of organic carbonyl chloride.
U.S. Pat. No. 6,770,783 teaches a method comprising introducing gaseous hydrogen chloride during or after the reaction of carboxylic acids with phosgene or thionyl chloride in the presence of a catalyst adduct of an N, N-disubstituted formamide to aid the physical separation of Vilsmeier salt and the acid chloride product.
A recent US Patent Application No. 2010/0099911 provides a method for producing a carboxylic acid chloride which involves decomposing the Vilsmeier complex. The method comprises adding 1.0-3.0 equivalents of the starting carboxylic acid, based on the amount of the catalyst, to the reaction product of a reaction between carboxylic acid and a chlorinating agent, to decompose the Vilsmeier reagent type compounds which remain in the reaction product.
It is very clear that the phase separation of catalyst complex is not a straight forward method and a variety of approaches are reported to make it more effective. The phase separation is not clean and some amount of catalyst complex remains dissolved in the product and that is why the efforts for the progressive improvement are reported in the above mentioned patent-literature. Some of the recent patents indicate that the catalyst amount employed are usually large and additional steps are reported for improving the phase separation like passing hydrogen chloride gas into the reaction mixture (U.S. Pat. No. 6,770,783) or introducing carboxamide hydrohalide (U.S. Pat. No. 6,727,384) or decomposing the catalyst complex by adding acid (US Patent Application No. 2010/0099911).
Recently, Koshti et al. reported a lipophilic carboxamide (U.S. Pat. No. 9,187,407) catalyst for chlorination of fatty acid to affect the homogeneous catalysis. This catalyst decomposes to give the surfactants in the subsequent step involving reaction with amino acids under Schotten Baumann conditions. However, this methodology is useful for making fatty acid chlorides that would be used up subsequently for the synthesis of N-acyl amino acid surfactants (sodium cocoyl glycinate, sodium cocoyl glutamate, sodium lauroyl sarcosinate or sodium cocoyl taurate etc.) because the residual catalyst gets converted into amino acid based surfactants in subsequent stage. In this process the proposed catalyst is not removed from the fatty acid chloride. It gets converted into surfactants during the second Schotten-Baumann step wherein fatty acid chlorides are reacted with amino acids in the presence of a base. So this is a special case of fatty acid chloride synthesis catalyzed by surfactants and not a universal procedure that can be adopted for a variety of acid chlorides that are aromatic (benzoyl chloride) or small chain aliphatic (pivaloyl chloride, valeryl chloride) or p-methoxy cinnamoyl chloride.
Alkyl Chlorides
Alkyl halides are key intermediate in organic synthesis. These are industrial bulk chemicals involved in the manufacture of variety of products that include drugs, dyes, surfactants and a host of fine chemicals. In terms of synthetic transformations, alkyl halides enable bond formation between carbon and oxygen, carbon and nitrogen and carbon and phosphorous. Using transition metal catalysis and organometallic reagents it is possible to form bond between sp3 hybridized carbons (reactions involving Grignard Reagent RMgX and other organic substrates such as carbonyl compounds, Grignard reagent in transition metal catalyzed reactions such as Kulinkovich cyclopropanation, Kumada reaction, other organometallic reagent from alkyl halide such as RZnCl (Negishi reaction)). Alkyl halides can be converted into nitriles, thiols, alkenes, alkynes and ethers etc.
Commercially, alkyl halides are manufactured by halogenations of alkanes and halogenation of alcohols. On large scale, alcohols of different chain lengths are available from petrochemical origin or vegetable origin. Alcohols are usually converted into the corresponding chlorides by gaseous hydrochloric acid, phosphorous trichloride, phosphorous pentachloride, phosphorous oxy chloride, phosgene and thionyl chloride. Alcohols are generally reacted with hydrochloric acid using catalysts like zinc chloride, generating water as by-product. When alcohols are reacted with halogenating agents like thionyl chloride or phosphorous trichloride then the by-products are sulphur dioxide and phosphorous acid respectively, in addition to common by-product of hydrochloric acid.
U.S. Pat. No. 2,331,681 describes the chlorination of glycolonitrile to chloroacetonitrile with thionyl chloride in the presence of the organic bases like pyridine and other tertiary amines such as dimethyl aniline or quinoline. The drawback of the process is the usage of equimolar amounts of catalyst that needs to be separated from the product, alkyl halide.
EP0645357 (1995) teaches a process for preparing alkyl chlorides from corresponding alcohols and stoichiometric amount of catalyst adduct (Vilsmeier salt). The catalyst adduct is formed from N, N-dimethyl formamide with thionyl chloride or phosgene. The disadvantage of this process is the use of equimolar amounts of catalyst.
GB2182039 (1985) discloses the chlorination of alcohols with thionyl chloride or phosgene in the presence of triphenylphosphine oxide or triphenylphosphine sulphide. Again, the amount of catalyst employed is near to stoichiometry.
DE4116365 (1991) teaches the preparation of alkyl, alkenyl and alkynyl chlorides by reacting the corresponding alcohols with phosgene or thionyl chloride in the presence of an aliphatic, cycloaliphatic or cyclic/aliphatic phosphine oxide as catalysts. However, these are very expensive and not readily available catalysts compared to triphenyl phoshine oxide.
U.S. Pat. No. 5,723,704 (1998) reports a two stage process for preparation of the alkyl chloride comprising reacting alcohol with gaseous hydrochloric acid at elevated temperature of 80 to 170° C. and under pressure, to achieve 60 to 90% conversion and then converting unreacted alcohol with phosgene in the presence of a catalyst. The catalyst is selected from guanidine and pyridine derivatives, quaternary ammonium halides and quaternary phosphonium halides.
US 2008228016 (2005) teaches real catalytic quantity of triphenylphosphine oxide catalyst (0.0001 to 0.5 mole equivalent of corresponding alcohol) and thionyl chloride. It uses higher temperature and pressure (0.01 to 10 mPa abs.) for the catalytic chlorination.
U.S. Pat. No. 6,245,954 (2001) teaches alkyl halide from alcohol using phosgene or thionyl chloride under catalysis by urea derivatives. The patent teaches reaction at temperatures of 120-130° C. This process is an example of homogeneous catalysis with substituted urea derivatives as catalyst. After the reaction, the insoluble impurities can be filtered off. However, for soluble impurities subsequent purification steps like distillation are needed. The same process limitation is reported with catalysts like triphenyl phosphine or phosphonium sulphide (GB182039) and other aliphatic phosphorous compounds (EP514683) which are difficult to remove and the residue after distillation containing phosphorous compounds are difficult to dispose off.
Hydrochloric acid is also a preferred industrial chlorinating agent. A number of processes are reported by patented literature using HCl and aqueous alkyl pyridine hydrochloride solutions as catalysts (EP0789013, DE10158376 and DE10247497). Alkyl halides made by these processes are purified by very complex procedure involving extraction, filtration though silica gel and subsequent distillation.
JPS53015303 describes the preparation of alkyl halides by reacting alcohols with an aqueous solution of hydrogen halide in the presence of quaternary ammonium compounds as a catalyst. Primary alcohols are chlorinated with aqueous hydrochloric acid in micellar medium (Synthesis 11, 868-871 (1988)) in the presence of quaternary ammonium surfactants. The isolation of quaternary ammonium compound is necessary for obtaining clean product.
U.S. Pat. No. 7,652,180 (2010) reports an improved procedure using gaseous HCl and substituted N-pyridinium chloride or N-substituted and C-substituted imidazolidium chlorides as catalysts. Reaction is carried out at a temperature of 60-160° C. The biphasic reaction product is separated; organic phase is worked up and is finally distilled to give alkyl halide.
Formamide or carboxamide type of catalysts or tertiary amines or any other soluble catalysts (homogeneous catalysis) that are used for chlorination of alcohols have same difficulty of isolation of product from the catalyst-product mix that results at the completion of reaction.
Thus, there is a need in the art for an improved process wherein the catalyst can be cleanly isolated from the products (acid chlorides or alkyl chlorides) and can be recycled a number of times without losing its catalytic efficiency. The clean and quantitative isolation of the catalyst would avoid subsequent steps of purification like distillation or crystallization and the waste generated. Because, these additional purification steps result in significant loss of yield, higher energy consumption and longer batch cycle time resulting into lower productivity.